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Proc. Natl. Acad. Sci. USA, Published online before print December 19, 2014, doi: 10.1073/pnas.1413687112 RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells.

Abstract

Tae-Yoon Park^a, Sung-Dong Park^a, Jen-Young Cho^a, Jae-Seung Moon^a, Na-Yeon Kim^a, Kyungsoo Park^b, Rho Hyun Seong^b, Sang-Won Lee^c, Tomohiro Morio^d, Alfred L. M. Bothwell^e, and Sang-Kyou Lee^a,1

^aDepartment of Biotechnology, College of Life Science and Biotechnology, Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea; ^bDepartment of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea; ^cDivision of Rheumatology, Department of Internal Medicine, Institute for Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea; ^dDepartment of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; and ^e Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520

Abstract

The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORγt) is a transcription factor (TF) specific to T_H17 cells that produce interleukin (IL)-17 and have been implicated in a wide range of autoimmunity. Here, we developed a novel therapeutic strategy to modulate the functions of RORγt using cell-transducible form of transcription modulation domain of RORγt (tRORγt-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tRORγt-TMD specifically inhibited T_H17-related cytokines induced by RORγt, thereby suppressing the differentiation of naive T cells into T_H17, but not into T_H1, T_H2, or T_reg cells. tRORγt-TMD injected into experimental autoimmune encephalomyelitis (EAE) animal model can be delivered effectively in the splenic CD4⁺ T cells and spinal cord-infiltrating CD4⁺ T cells, and suppress the functions of T_H17 cells. The clinical severity and incidence of EAE were ameliorated by tRORγt-TMD in preventive and therapeutic manner, and significant reduction of both infiltrating CD4⁺ IL-17⁺ T cells and inflammatory cells into the CNS was observed. As a result, the number of spinal cord demyelination was also reduced after tRORγt-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking T_H1 differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tRORγt-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with T_H17 or T_H1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis.

Footnotes

¹To whom correspondence should be addressed.

논문정보

형식Research article
게재일2014년 12월 (BRIC 등록일 2014-12-23)
연구진국내(교신)+국외 연구진
분야 생명과학 > 면역학

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